Severe viral diseases are caused by a combination of virus-mediated cytopathic effects and either an acutely overactive or chronic inflammatory response. Diseases, such as keratoconjunctivitis by HSV1 or Adenovirus, encephalitis by HSV2 (in neonates) or West Nile virus, and emerging pandemic diseases, such as SARS and influenza, frequently cause severe complications and disabilities. These include blindness, severe mental retardation, pneumonia, acute respiratory distress and even death. Current therapies, when available, rely almost entirely on virus-specific antiviral drugs. However, elimination of the virus by antivirals does not prevent the inflammatory complications that result ultimately in disease manifestations. Therefore, corticosteroids are often used when inflammatory complications ensue. Corticosteroids, however, frequently lead to increased viral replication or reactivation of latent virus, thereby resulting in a difficult to interrupt vicious ycle. No single drug currently exists that can both inhibit viral replication and control deleterious inflammation. Our data, however, support a paradigm shifting hypothesis where simple and achievable metabolic changes in the tissue microenvironments can concurrently inhibit viral replication, modulate the inflammatory and angiogenic responses, and promote tissue healing, while allowing the development of a protective immune response. The depletion of the amino acids arginine or tryptophan by the enzymes arginase 1 (Ase-1) and indoleamine 2,3- dioxygenase (IDO) is one of the mechanisms by which the immune system regulates the magnitude of its response and prevents collateral damage to normal tissues during inflammation. It is also a mechanism frequently hijacked by tumors to escape an anti-tumor immune response. Here, we show that the in vivo depletion of a single amino acid has a potent and unexpected therapeutic effect in treating severe viral diseases. Arginine depletion inhibited a broad range of viral replication and promoted healing of tissues, while concurrently modulating deleterious inflammation and disease-associated neovascularization. This paradigm shifting observation leads us to propose that understanding the immunological and molecular pathways by which this therapeutic process occurs will not only create a new understanding of the metabolic mechanisms operating during severe viral and inflammatory diseases, but also create a platform for the development of novel therapies utilizing these natural immunoregulatory pathways.
Severe viral diseases such as infections of the cornea by Herpes virus and adenovirus, encephalitis by West Nile virus, and pandemic influenza cause serious complications and frequently result in permanent disabilities. The disease is caused by the combined effect of the viral infection and an overactive immune response and current anti-viral drugs do not always prevent the damaging effects of the disease. Therefore, it is important to find a treatment that can inhibit the growth of the virus and control inflammation while allowin for the development of protective and long lasting immunity;simple and achievable metabolic changes can provide both effects and promote healing of the tissues.
|Lassak, Adam; Dean, Mathew; Wyczechowska, Dorota et al. (2018) Molecular and Structural Traits of Insulin Receptor Substrate 1/LC3 Nuclear Structures and Their Role in Autophagy Control and Tumor Cell Survival. Mol Cell Biol 38:|
|Al-Khami, A A; Ghonim, M A; Del Valle, L et al. (2017) Fuelling the mechanisms of asthma: Increased fatty acid oxidation in inflammatory immune cells may represent a novel therapeutic target. Clin Exp Allergy 47:1170-1184|
|Rodriguez, Paulo C; Ochoa, Augusto C; Al-Khami, Amir A (2017) Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity. Front Immunol 8:93|
|Al-Khami, Amir A; Rodriguez, Paulo C; Ochoa, Augusto C (2017) Energy metabolic pathways control the fate and function of myeloid immune cells. J Leukoc Biol 102:369-380|
|Al-Khami, Amir A; Zheng, Liqin; Del Valle, Luis et al. (2017) Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells. Oncoimmunology 6:e1344804|
|Sanchez, Maria Dulfary; Ochoa, Augusto C; Foster, Timothy P (2016) Development and evaluation of a host-targeted antiviral that abrogates herpes simplex virus replication through modulation of arginine-associated metabolic pathways. Antiviral Res 132:13-25|
|Hossain, Fokhrul; Al-Khami, Amir A; Wyczechowska, Dorota et al. (2015) Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies. Cancer Immunol Res 3:1236-47|
|Crittenden, Marka R; Savage, Talicia; Cottam, Benjamin et al. (2014) Expression of arginase I in myeloid cells limits control of residual disease after radiation therapy of tumors in mice. Radiat Res 182:182-90|
|Dimitriades, Victoria; Rodriguez, Paulo C; Zabaleta, Jovanny et al. (2014) Arginase I levels are decreased in the plasma of pediatric patients with atopic dermatitis. Ann Allergy Asthma Immunol 113:271-5|
|Garvey, Cathryn E; McGowin, Chris L; Foster, Timothy P (2014) Development and evaluation of SYBR Green-I based quantitative PCR assays for herpes simplex virus type 1 whole transcriptome analysis. J Virol Methods 201:101-11|
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